The landmark Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) has refocused attention on the thiazide-type diuretics as the first-line therapy for most patients with hypertension. Despite proven reduction in cardiovascular outcomes and low costs, there is on-going concern that one of the major side effect of the thiazides--glucose intolerance--may fuel the current U.S. epidemic of type 2 diabetes, the long-term cardiovascular impact of which is underestimated in the typical 5 year duration of a hypertension trial. After decades of clinical use, we still do not know how thiazide diuretics cause glucose intolerance. My pilot data lead me to hypothesize that (a) these drugs trigger reflex sympathetic activation in the skeletal muscle, a major site of insulin-mediated glucose disposal and (b) the sympathetic activation and the glucose intolerance can be avoided by using mineralocorticoid receptor antagonists rather than thiazide diuretics as first-line therapy for hypertension. Accordingly, we will test, in a large multiethnic cohort of hypertensive subjects, whether chlorthalidone causes a sustained increase in muscle sympathetic nerve activity (SNA), promoting neurogenic vasoconstriction and reducing glucose extraction by skeletal muscle and if spironolactone avoids such sympathetic activation and the resultant glucose intolerance. The distinctive features of this proposal include the: (1) use of state-of-the-art techniques in integrative physiology; (2) focus on the functional role of muscle sympathetic nerve activity on skeletal muscle glucose uptake and total body insulin sensitivity; and (3) the focus on modulation of central sympathetic outflow by MR antagonist, which traditionally has been viewed simply as a potassium sparing diuretic agent. This translational research should fill in some important gaps in our mechanistic understanding of the thiazidediuretics induced insulin resistance and offer a strategy to avoid such neurohormonal activation and metabolic complications while preserving antihypertensive efficacy with spironolactone.